Fluconazole analogues containing 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moieties,a novel class of anti-Candida agents

As a part of our program to develop new antifungal agents, a series of fluconazole analogues was designed and synthesized wherein one of the triazole moieties in fluconazole was replaced with 2H-1,4-benzothiazin-3(4H)-one or 2H-1,4-benzoxazin-3(4H)-one moiety. The new chemical entities thus synthesized were screened against various fungi and it was observed that the compounds 4a and 4i are potent inhibitors of Candida strains. The structure–activity relationship for these compounds is discussed.     

Chemical constituents from the roots of Acanthus ilicifolius var. xiamenensis

Chemical investigation of Acanthus ilicifolius var. xiamenensis led to the isolation of eleven compounds, and their structures were identified to be 2-benzoxazolinone (1), 2-hydroxy-2H-1,4-benzoxazin-3(4H)-one (2), (2R)-2-O-β-d-glucopyranosyl-2H-1,4-benzox azin-3(4H)-one (3), (2R)-2-O-β-d-glucopyranosyl-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one (4), (2R)-2-O-β-d-glucopyranosyl-7-hydroxy-2H-1,4-benzoxazin-3(4H)-one (5), lyoniside (6), 3′-methoxy-luteolin-7-O-β-d-glucopyranoside (7), β-sitosterol-3-O-β-d-glucopyranoside (8), stigmasterol octadecanoate (9), β-sitosterol octadecanoate (10), stigmasterol-3-O-β-d-glucopyranoside (11) on the basis of mass and NMR spectra. This is the first report on the occurrence of compound 6 and 7 in Acanthaceae. This work also represents the first phytochemical work on the roots of A. ilicifolius var. xiamenensis.     

<Emphasis Type="Italic">ScBx</Emphasis> gene based association analysis of hydroxamate content in rye (<Emphasis Type="Italic">Secale cereale</Emphasis> L.)

Hydroxamates (HX) are major secondary metabolites synthesized by rye and are responsible for some of the unique properties of this cereal, including good tolerance of biotic and abiotic stresses and allelopathy. Recently, five genes encoding enzymes taking part in HX biosynthesis have been sequenced and characterized, which was the starting point to undertake the present study. Association analysis of the content of six HX–HBOA (2-hydroxy-1,4-benzoxazin-3-one), GDIBOA (2,4-dihydroxy-1,4-benzoxazin-3(4H)-one glucoside), DIBOA (2,4-dihydroxy-1,4-benzoxazin-3(4H)-one), GDIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3(4H)-one glucoside), DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3(4H)-one) and MBOA (6-methoxy-benzoxazolin-2(3H)-one) in the above-ground parts of plants and roots was performed on a population consisting of 102 and 121 diverse inbred lines, in 2013 and 2014, respectively. Altogether, 48 single nucleotide polymorphisms (SNPs) were found to be associated with the content of at least one HX: 20 SNPs were associated with HX synthesized in the above-ground parts of rye plants (AG-SNP), and 28 were associated with HX synthesized in the roots (R-SNP). The highest number of SNPs was present in genes ScBx1 (9) and ScBx5 (11). The majority of SNPs were affected by environmental factors, except for two: ScBx4_1702 associated with GDIBOA and MBOA contents, and ScBx5_1105 associated with HBOA content in roots.     

Symmetrical α-bromoacryloylamido diaryldienone derivatives as a novel series of antiproliferative agents. Design,synthesis and biological evaluation

In a continuing study of hybrid compounds containing the α-bromoacryloyl moiety as potential anticancer drugs, we synthesized a novel series of hybrids 4a–h, in which this moiety was linked to a 1,5-diaryl-1,4-pentadien-3-one system. Many of the conjugates prepared (4b, 4c, 4e and 4g) demonstrated pronounced, submicromolar antiproliferative activity against four cancer cell lines. Moreover, compound 4b induced apoptosis through the mitochondrial pathway and activated caspase-3 in a concentration-dependent manner.     

Synthesis of new heterocyclic hybrids based on pyrazole and thiazolidinone scaffolds as potent inhibitors of tyrosinase

As a part of ongoing studies in developing new Tyrosinase inhibitors, a class of structurally novel 2-(2,4-dimethoxy phenylamino)-5 methylene-4-thiazolinone derivatives were synthesized by incorporating 2-(2,4-dimethoxy-phenylamino)-thiazol-4-one with various 1-(1-methyl-buta-1,3-dienyl)-3-phenyl-1H-pyrazole-4-carbaldehyde. The results showed that some of the synthesized compounds exhibited significant inhibitory activities. Especially, 5-[3-(2-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5h) and 5-[3-(3-chloro-phenyl)-1-phenyl-1H-pyrazol-4-ylmethylene]-2-(2,4-dimethoxy-phenylamino)-thiazol-4-one (5g) possessing 2-chloro-phenyl and 3-chloro-phenyl group exhibited the most potent tyrosinase inhibitory activity with an IC₅₀ value of 34.12 and 52.62 μM, respectively. The inhibition mechanism analysis of 5h and 5g thiazolidinone derivatives demonstrated that the inhibitory effects of the compounds on tyrosinase were reversible and competitive. Preliminary structure–activity relationships (SAR) analysis suggested that further development of such compounds might be of interest, as it manifests simple reversible slow binding inhibition against monophenolase and diphenolase.     

Identification of 1,4-Benzoxazin-3-ones in Maize Extracts by Gas-Liquid Chromatography and Mass Spectrometry

Gas-liquid chromatography-mass spectrometry (GLC-MS) has been used for the separation, detection, and identification of 1,4-benzoxazin-3-ones (hydroxamic acids and lactams) and benzoxazolinones found in maize (Zea mays L.) extracts. Compounds of interest were partitioned into ethyl acetate from aqueous maize seedling extracts. For analysis by GLC-MS, trimethylsilyl derivatives were prepared, chromatographed on a column of 3% OV-1, and detected in the mass spectrometer. Mass spectra were obtained for all peaks present in extracts of four maize lines. A data comparison system was developed for relating unidentified spectra to the spectra of the reference compounds. Based on spectral comparisons, three hydroxamic acids (2,4-dihydroxy-2H-1, 4-benzoxazin-3(4H)-one; 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one; and 2,4-dihydroxy-7,8-dimethoxy-2H-1,4-benzoxazin-3(4H)-one), three lactams (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one; 2,7-dihydroxy-2H-1,4-benzoxazin-3(4H)-one; and 2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), one benzoxazolinone (6-methoxybenzoxazolinone), and two organic acids (malic and aconitic) were identified in the extracts. In addition, one other hydroxamic acid and one other related compound were tentatively identified based on mass spectral evidence.     

Synthesis and biological evaluation of 3-acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives as potential MERS-CoV inhibitors

3-Acyl-2-phenylamino-1,4-dihydroquinolin-4(1H)-one derivatives were synthesized and evaluated to show high anti-MERS-CoV inhibitory activities. Among them, 6,8-difluoro-3-isobutyryl-2-((2,3,4-trifluorophenyl)amino)quinolin-4(1H)-one (6u) exhibits high inhibitory effect (IC₅₀ = 86 nM) and low toxicity (CC₅₀ > 25 μM). Moreover, it shows good metabolic stability, low hERG binding affinity, no cytotoxicity, and good in vivo PK properties.     

1,2-Benzisothiazol-3-one derivatives as a novel class of small-molecule caspase-3 inhibitors

A novel series of 1,2-benzisothiazol-3-one derivatives was synthesized and their biological activities were evaluated for inhibiting caspase-3 and -7 activities, in which some of them showed low nanomolar potency against caspase-3 in vitro and significant protection against apoptosis in a camptothecin-induced Jurkat T cells system. Among the tested compounds, compound 5i exhibited the most potent caspase-3 inhibitory activity (IC₅₀ = 1.15 nM). The molecular docking predicted the interactions and binding modes of the synthesized inhibitor in the caspase-3 active site.     

Quantitation of 1,4-Benzoxazin-3-ones in Maize by Gas-Liquid Chromatography

A gas-liquid chromatographic (GLC) procedure is reported for the quantitation of the trimethylsilyl (TMS) derivatives of substituted 2-hydroxy-2H-1,4-benzoxazin-3(4H)-ones (2-hydroxy-2H-1,4-benzoxazin-3(4H)-one[HBOA]; 2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one[HMBOA];2,4- dihydroxy-2H-1,4-benzoxazin-3(4H)-one[DIBOA]; 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one[DIMBOA]; and 2,4-dihydroxy-7,8-dimethoxy-2H-1,4-benzoxazin-3(4H)-one[DIM ₂BOA]) found in maize (Zea mays L.) extracts. Derivatized samples were chromatographed on columns with liquid phases of 2% DC-11 and 3% OV-17 and detected by flame ionization. Internal standards were methyl palmitate and methyl stearate on DC-11 and methyl behenate on OV-17. Detector response was linear to at least 5 nanomoles for TMS₂-HBOA and TMS₂-DIBOA and to 19 nanomoles for TMS₂-DIMBOA. Standard errors of 2% or less were obtained when four replicate samples were analyzed. For each of the 15 maize lines examined, the amount of DIMBOA determined by GLC was directly proportional to the amount of ferric chloride-reactive material determined colorimetrically.     

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

New pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC₅₀ against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines.     

3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents

Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette–Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure–activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC₉₀ value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.     

Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors

Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC₅₀ values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.     

Effects of four benzoxazinoids on gibberellin-induced alpha-amylase activity in barley seeds

Germination of barley seeds was inhibited by 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA) and 2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one (DIBOA) at concentrations greater than 0.03mmol/L, and 6-methoxy-benzoxazolin-2(3H)-one (MBOA) and benzoxazolin-2(3H)-one (BOA) at concentrations greater than 0.1mmol/L. These benzoxazinoids also inhibited the induction of alpha-amylase activity in the barley seeds, and inhibited gibberellin-induced alpha-amylase activity in de-embryonated barley seeds. Significant inhibition in the germination and alpha-amylase induction were observed as concentrations of DIMBOA, DIBOA, MBOA and BOA increased. These results suggest that DIMBOA, DIBOA, MBOA and BOA may inhibit the germination of barley seeds by inhibiting the gibberellin-induced process, leading to alpha-amylase production. The inhibitory activities of germination and alpha-amylase induction of DIMBOA and DIBOA were greater than those of their degraded substances MBOA and BOA, respectively, and the inhibitory activities of DIMBOA and MBOA were greater than those of their demethoxylated analogues DIBOA and BOA, respectively.     

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.     

Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC₅₀ values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.     

Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents

A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC₅₀?=?3.73?nM) and is a promising candidate for further development in therapeutics for cancer.     

Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα

PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kβ, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor.     

Discovery of novel benzo[b][1,4]oxazin-3(4H)-ones as poly(ADP-ribose)polymerase inhibitors

Structure based drug design of a series of novel 1,4-benzoxazin-3-one derived PARP-1 inhibitors are described. The synthesis, enzymatic & cellular activities and pharmacodynamic effects are described. Optimized analogs demonstrated inhibition of poly-ADP-ribosylation in SW620 tumor bearing nude mice through 24 h following a single dose.     

Synthesis and biological evaluation of novel trichodermin derivatives as antifungal agents

To discover more potential antifungal agents, 17 novel trichodermin derivatives were designed and synthesized by modification of 3 and 4a. The structures of all the synthesized compounds were confirmed by ¹H NMR, ESI-MS and HRMS. Their antifungal activities against Ustilaginoidea oryzae and Pyricularia oryzae were evaluated. Most of the target compounds showed potent inhibitory activity, in which 4g showed superior inhibitory effects than 4a and commercial fungicide prochloraz. Furthermore, 4h demonstrated comparable inhibitory activity to 4a. Moreover, 4i and 4l exhibited excellent inhibitory activity for Pyricularia oryzae. Additionally, compound 9 was found to be more active against all tested fungal strains than 3, with EC₅₀ values of 0.47 and 3.71 mg L⁻¹, respectively.